Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 47, Num. 2, 2010, pp. 100-119

Indian Journal of Cancer, Vol. 47, No. 2, April-June, 2010, pp. 100-119

Symposium

Clinical applications of positron emission tomography-computed tomography in oncology

Kumar R, Halanaik D, Malhotra A

Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi

Correspondence Address:Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi rkphulia@yahoo.com

Code Number: cn10032

PMID: 20448371

DOI: 10.4103/0019-509X.62997

Abstract

Keywords: Fluorodeoxyglucose, oncology, positron emission tomography - computed tomography

Introduction

Positron emission computed tomography (PET) is a functional diagnostic imaging technique, which has ability to study various biological processes like glucose, amino acid, phospholipids, receptors etc. Addition of CT to PET has shown better specificity and sensitivity than either PET or CT alone as it has the ability to demonstrate functional and structural details in the same setting. The main objectives of oncologic imaging are lesion detection, lesion characterization, evaluation of the extent of the tumor, initial staging, assessment of the treatment response and detection of recurrent disease. The most widely used radiotracer in PET for this purpose is Fluorine18-fluorodeoxyglucose (FDG), which is an analogue of glucose. The uptake of FDG is mediated by a family of structurally related glucose transporter proteins (GLUT receptors) present on cell membrane. ^[1] Subsequently, it is phosphorylated by the enzyme hexokinase to FDG-6-phosphate. ^[2],[3],[4] However, FDG-6-phosphate is biochemically trapped within the cell since it is not a substrate for glucose-6-phosphate isomerase.

PET-CT have a very high sensitivity and a high negative predictive value for lesion detection as compared to conventional morphological modalities like computed tomography (CT), ultrasonography (USG) and magnetic resonance imaging (MRI). The role of PET has been already established in initial staging, monitoring the response to the therapy and recurrence detection of various important cancers. Recent data show that PET-CT has higher sensitivity and specificity as compared to PET and CT alone as it provides better characterization and localization of lesion. Unfortunately, FDG is not a cancer specific agent and its uptake has been described in a number of non-neoplastic inflammatory lesions like sarcoidosis, tuberculosis, fungal infection and abscesses. ^[5],[6] The applications of PET and PET-CT in major malignancies will be discussed in this review.

Normal Biodistribution of FDG and its Variants

It is always important to know the normal biodistribution and variants for the correct interpretation of any imaging modality. Therefore, it is also important to know the normal distribution of FDG for correct interpretation of PET-CT. Tensing muscles are one of the common sites of physiological FDG uptake. Patients undergoing PET/PET-CT scan, hence, should be advised to refrain from exercise, chewing and talking before and immediately after injection of F-18 FDG. Muscle uptake can also be noted in patients who fasted less than four hours. The uptake is generally symmetrical but sometimes can be asymmetrical, especially in torticollis, after surgery and unilateral paralysis. Mild sedation may be needed in anxious patients to avoid skeletal muscle uptake. In our experience, oral administration of single dose of 40 mg of beta blocker one hour before FDG injection is also effective in reducing muscle uptake. Brown fat also shows intense FDG uptake and usually presents as bilateral symmetrical uptake [Figure - 1]. Sometimes it is difficult to interpret normal asymmetrical FDG uptake in muscles and brown fat with PET alone. However, with the PET-CT, uptake in muscles and brown fat rarely pose difficulty in interpretation.

FDG uptake in the gastrointestinal tract (GIT) is variable and is mainly due to smooth muscle activity associated with peristalsis, uptake in mucosa and normal bacterial flora of intestine. In addition, PET-CT shows increased FDG uptake because of overestimation of activity in view of the collapsed wall of the colon. There can be normal mild FDG activity in the esophagus, possibly due to swallowed saliva or smooth muscle metabolism. Stomach is usually seen and there can be intense FDG uptake in the pyloric end of stomach due to contraction (hunger pains). Uptake in the cecum and right colon is usually higher than in other colonic segments. In our experience, modified technique called PET-CT enteroclysis, wherein intestine is inflated with oral ingestion of polyethylene glycol, is useful. Due to dilatation GIT, it is easy to differentiate between physiological and abnormal FDG uptake. Unlike glucose, FDG is not totally reabsorbed in the kidneys and activity in the urinary tract may interfere with the interpretation of malignant tumors arising from kidneys, ureters, urinary bladder, cervix, ovary etc. Improvement in imaging can be made using intravenous lasix and proper hyderation. Glandular breasts show moderate activity, especially in premenopausal women and in women taking estrogen pills. This may obscure potential lesions in the breast. Uptake in the bone marrow, spleen and other reticuloendothelial organs may be significant after therapy with colony stimulating factors. Lymphoid tissues in head and neck also show increased FDG uptake which usually symmetrical.

Standardized Uptake Value

In addition to qualitative image display, it is possible to quantify specific uptake value normalized to the injected dose, which is called "standardized uptake value" (SUV). The SUV provides an approximate indicator that correlates with FDG metabolism in the tissue. During the initial years, a SUV of 2.5 was considered by many as a cutoff value to differentiate between benign and malignant diseases. An abnormality with SUV more than 2.5 used to was considered malignant. However, learning with time, it is now not valid in the practice of PET. In countries where the incidence of infectious and inflammatory disease is higher, this cutoff value of 2.5 does not work. In our experience, many a time, significantly higher SUVs were noted in infection and inflammation.

Clinical Applications

Solitary Pulmonary Nodule

Conventional imaging modalities such as chest radiography and CT have secured an essential role in solitary pulmonary nodules. ^[7],[8] Based on various imaging patterns, CT can often differentiate benign and malignant conditions. However, on many occasion, these techniques cannot differentiate the two conditions. Chest MRI has been used in the evaluation of lung masses as well, but this technique is suboptimal. ^[9] FDG PET and PET-CT can provide additional information and have been successfully used as non-invasive diagnostic tests for solitary pulmonary nodules (SPN) in order to differentiate benign lesions from malignancy. ^[10] In one study, 56 patients were evaluated for SPN with FDG PET/CT, of which 26 were true positive, five false positive, 24 true negative and one false negative. In this study, the presence of any FDG avidity was more sensitive than semi quantitative analysis for malignancy. ^[11]

False Positive : Most benign pulmonary nodules do not accumulate FDG. However, active granulomatous infections like tuberculosis, sarcoidosis, histoplasmosis or coccidioidomycosis can demonstrate increased FDG uptake. Recent studies have shown better results with delayed PET images taken several hours after FDG injection (dual time point imaging), along with routine one-hour imaging protocol. These studies conclude that malignant nodules show increased FDG uptake over time, while pulmonary nodules of benign origin have a declining pattern of uptake with time. ^[12]

False Negative : Low-grade tumors like bronchoalveolar cell carcinoma and bronchial carcinoid, may not show increased FDG uptake on dedicated PET/ PET-CT scans. ^[13],[14] In addition, very small lesions (less than 5 mm) can be missed on PET and PET-CT as scanning is done without breath holding, these lesions show lower SUVs due to partial volume effect. ^[12]

Lung Cancer

As of today, CT is the imaging modality of choice to define the extent of the primary tumor and to assess the tumor involvement of the pleural surfaces and the thoracic wall. ^[15] Mediastinoscopy, CT and MRI are being used for assessing the involvement of lymph nodes. Barring thoracotomy, mediastinoscopy is considered the gold standard for lymph node staging. However, it is an invasive procedure and is also prone to under-coverage and sampling errors. ^[16],[17] The main limitation of CT and MRI is using a size criterion of 1 cm for the diagnosis of tumor involvement. Since FDG-PET imaging depends on increased metabolism of the malignant cells, it can be used successfully in order to differentiate malignant nodes from others. However, sometimes, infectious and inflammatory lymph nodes also show increased FDG.

A vast majority of the FDG-PET studies for lung cancer have been done in non-small cell lung cancer (NSCLC) patients in whom regional and distant involvement of the disease will change staging and guide the therapeutic approach. Combined PET-CT scan is very useful in providing the relevant information regarding local tumor extension as well as distant metastatic lesions [Figure - 2]. The presence of FDG uptake in the pleural space is a bad prognostic sign compared to benign effusion. ^[18],[19] Whole body PET-CT scan is very useful as it covers the most common sites of metastatic disease, e.g. lung, liver, brain, adrenals, and bone etc. FDG PET/CT study was conducted in 42 patients with clinicoradiological suspicion of recurrence in carcinoma lung patients. Twenty-four of the 27 patients were true positive, 14/15 patients had true negative with sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), fairly superior compared to alone PET or CT. ^[20] Overall, PET/CT is able to detect the disease at both local as well as distant sites, which may not be apparent by standard imaging strategies in 10-14% of cases and, therefore, can change management in many patients. ^[21],[22] FDG-PET can eliminate the need for biopsy of enlarged adrenal glands in lung cancer patients and found to have more than 90% accuracy for adrenal involvement. ^[23],[24]

FDG-PET also has a role in the assessment of prognosis and treatment in lung cancer patients. ^[25] FDG PET/CT performed after one cycle of chemotherapy in 36 patients with advanced or metastatic lung cancer shows there was early detection of progressive disease compared to conventional imaging modalities. Thus unnecessary systemic chemotherapy can be avoided in this group of patients. ^[26] Cost-effectiveness has been a major concern in PET imaging. Some studies have looked into the cost-effectiveness of FDG-PET in staging non-small cell lung cancer. These studies conclude that elective use of FDG-PET imaging makes it a feasible, safe and cost saving adjunct to the preoperative staging of NSCLC. ^[27]

Colorectal Carcinoma

Colorectal carcinoma is the third most common malignancy in both men and women and the third leading cause of all cancer deaths. Colonoscopy followed by biopsy remains the corner stone in the diagnosis of colorectal carcinoma. Preoperative staging, with imaging modalities, is usually limited because the extent of the disease can be evaluated during surgery and most patients will benefit from colectomy to prevent intestinal obstruction. Although the sensitivity of FDG-PET for the preoperative diagnosis of colorectal carcinoma is high, in practice, it has no important role since surgical diagnosis and staging will be needed for all patients. However, PET/CT may be advocated in a group of patients who show inconclusive metastatic lesions on CT [Figure - 3]. Three systematic reviews analyzed up to 32 studies which were conducted up to 2004. The most recently published systematic review reported that for extra hepatic lesions, the sensitivity and specificity of FDG PET were 92% and 95%, respectively. The sensitivity and specificity of CT for extra hepatic lesions were 61% and 91%, respectively. When data were pooled from the six studies that had the highest quality scores, the sensitivity and specificity of PET for extra hepatic lesions were 91% and 98%, respectively. For CT, sensitivity and specificity were 55% and 96%. PET resulted in a change in clinical management 32% (range, 20%-58%) of the time in 13 studies. In the six studies with the highest quality scores, the mean change in management was 25% (range, 20%-32%). ^[28] PET/CT with dedicated CT protocols such as contrast enhanced PET/CT and PET/CT colonography may replace the diagnostic CT in pre-operative staging.

FDG-PET is found to be superior to CT for the identification of liver metastases. FDG PET/CT, CECT and MRI were compared in a study for colorectal liver metastases in 65 patients. PET/CT was superior to CECT in detecting unexpected liver metastases and extra hepatic lesions. However, MRI was superior for small liver metastases. ^[29] FDG-PET has also been investigated for evaluation of treatment response. FDG PET/CT was performed in 40 patients with advanced colorectal cancer to evaluate prognosis and neoadjuvant chemotherapy response. Delta SUV Max (absolute SUV Max.change) and response index (RI, percent SUV Max.change) were best predictive parameters in response evaluation. ^[30]

So far, CT has been commonly used to localize the site of possible recurrence which has lower sensitivity and specificity. A meta-analysis of 11 clinical reports and 577 patients determined that the sensitivity and specificity of FDG-PET in detecting recurrent colorectal cancer were 97% and 76% respectively. ^[31] PET/CT is superior to contrast enhanced CT for the detection of recurrent intrahepatic tumors after hepatectomy, extra hepatic metastases, and local recurrence at the site of the initial colorectal surgery ^[32] [Figure - 4].

False Positive: Patients with fistulas, abscesses, diverticulitis and, less frequently, adenomas can cause false positive results and should be kept in mind while reporting PET and PET-CT scan.

False Negative: Normal physiological activity in the intestine can obscure intestinal lesion with PET. However, with PET-CT there is improvement in detection of intestinal lesions. Mucinous adenocarcinoma and microscopic lymph node metastasis can cause false negative results in up to 20% of patients.

Breast Cancer

Breast cancer is the commonest cancer in Europe and USA and second commonest malignancy in India. Mammography is the most commonly used imaging technique for the diagnosis of primary tumor but has lower sensitivity in women with radiographically dense breasts and patients with breast implants. ^[33] MR imaging and US have limited value in differentiating benign abnormalities from malignancies. ^[34] FDG-PET and PET-CT play a very important role in the work up of breast cancer ^[35] [Figure - 5]. Though dense breasts show increased FDG uptake as compared to non-dense breast tissue, it does not effect the detection of the primary tumor in patients with dense breasts. ^[36] Dedicated PET breast imaging devices are being developed and may become clinically more important.

Metastasis to axillary lymph nodes is one of the most important prognostic factors in breast cancer patients. Even though FDG-PET can detect axillary node involvement, it has been shown to have limitations in detecting lymph node metastasis when compared to sentinel lymph node biopsy. ^[37],[38] However, a clearly positive FDG-PET in select patients with a high risk of nodal metastases carries high positive predictive value and may identify patients with evidence of nodal metastases. This could indicate the need for standard axillary nodal dissection and therapeutic approaches, rather than SLN biopsy. One study compared the diagnostic accuracy of all in one protocol of PET/CT mammography and whole body PET/CT with MR mammography and multimodality imaging algorithms in initial staging of 40 patients with breast cancer. It revealed that there was similar accuracy for PET/CT mammography and MR mammography in primary breast lesion and axillary lymph nodes detection. Only PET/CT detected extra axillary lymphnodal lesions and distant metastatic lesions seen with 100% sensitivity compared to 70% for multimodality algorithm [Figure - 6]. ^[39]

In assessing residual tumor after neo-adjuvant chemotherapy, FDG-PET and PET-CT has been reported to detect metabolic changes in breast cancer much earlier than conventional imaging and clinical examination after initiation of chemotherapy. ^{[40],[41],[42]} Stafford et al. used serial FDG-PET to evaluate the response of skeletal metastases to therapy and demonstrated strong correlation between the quantitative change in SUV and overall clinical assessment of response and change in tumor markers. ^[43] Locoregional and distant metastasis occurs in up to 35% of patients of breast cancer within 10 years of initial surgery. ^[44] Whole body PET/ PET-CT has emerged as a sensitive and noninvasive technique in the management of breast cancer. FDG PET/CT has superior sensitivity and specificity compared to alone PET and diagnostic contrast enhanced CT for lesion detection in suspected recurrent breast cancer patients. ^[45] However, in detecting bone metastasis variable degrees of sensitivity and specificity have been reported. ^[46] PET has a limited role in detecting bone metastasis in the skull due to high uptake in the brain. The combination of FDG-PET scan and bone scan can be used for better sensitivity and specificity for bone metastases in these patients.

False Positive: Benign breast diseases like abscesses, tuberculosis, and fungal infections can be metabolically active resulting in false positive PET/PET-CT findings. Post surgical inflammatory changes can also cause false positive results due to higher FDG uptake.

False Negative: Patients with carcinoma, in situ, low-grade tumors, well differentiated ductal and lobular breast cancer, usually have significantly lower small unilamellar vesicles (SUVs) and can be misinterpreted as benign lesions. In addition, smaller lesions (< 5 mm) can be missed by PET/PET-CT images as they have lower SUVs due to partial volume effect. Axillary lymph nodes with micrometastsis and macrometastsis (smaller number of tumor cells) usually have false negative results.

Lymphoma

FDG-PET/ PET-CT is emerging as a powerful imaging modality for diagnosis, staging, and treatment monitoring of lymphoma patients. ^[47],[48] All histological types of non-Hodgkin′s lymphoma (NHL) can be successfully imaged with FDG-PET, with no significant difference in SUV among different sites and grades of disease both in Hodgkin′s disease (HD) and aggressive NHL [Figure - 7]. ^[48] For some subtypes of low-grade lymphoma (follicular, small lymphocytic and probably mantle cell lymphoma), the routine use of PET is still an issue that needs further evaluation.

FDG PET/PET-CT can detect more lesions than CT and may lead to a change in the stage of up to 15% of patients. ^[49],[50] A number of studies have assessed the value of PET in the diagnosis of extra nodal involvement like bone marrow, osseous, gastrointestinal and splenic involvement, which may be present in 10-25% of newly diagnosed patients of lymphoma ^[51],[52] [Figure - 8]. Another major advantage of FDG-PET/CT is that since it is a whole body imaging method, it can guide for the biopsy or histopathological examination from suitable and easily accessible site.

Approximately two-thirds of patients with HD and 50% of patients with NHL show persistent mass lesion on morphological imaging modalities after treatment, however FDG PET/CT shows absence metabolic activity in these lesions and lower incidence of relapse in these group of patients [Figure - 9]. ^[53] FDG-PET is very efficient and the precise fusion of morphologic and metabolic imaging data using hybrid PET-CT systems is useful for the management of a residual mass after therapy of lymphoma. ^[54]

False Positive: Benign inflammatory/infective diseases show increased lymph node uptake and cause false positive PET/PET-CT results. Post surgical/radiotherapy/chemotherapy inflammatory changes can also cause false positive results due to higher FDG uptake. Therefore, it is advisable to wait for six to eight weeks after these interventions. Postchemotherapy bone marrow stimulation can result in high SUV in bone marrow and cause difficulty in interpretation.

False Negative: Low-grade lymphoma (small lymphocytic and probably mantle cell lymphoma), follicular lymphoma and CNS lymphoma can cause false negative results. Lymph nodes with smaller number of tumor cells especially after completion of chemotherapy can cause false negative results in up to 20% of cases.

Head and Neck Cancer

Head and neck cancer is the most common type of cancer in India. Unfortunately, at the time of initial presentation, most of the patients (45%) present with regional nodes or even distant metastases. Patients with cervical lymph node metastasis from an unknown primary tumor present a big diagnostic dilemma. ^[55],[56] It is suggested that these patients undergo thorough examination and investigations to find out the primary site and treat accordingly. FDG-PET and PET-CT can be valuable tools in this subset of patients with an occult primary tumor in the head and neck region, as early identification of the primary tumor may allow more accurate tumor staging and targeted radiotherapy.

Lymph node metastasis in head and neck tumors is associated with poor prognosis. Accurate pre therapy lymph node staging is essential for therapeutic planning. FDG PET/CT has clear potential to affect patient management compared to PET alone and conventional morphological imaging like CT/MRI and avoids unnecessary neck surgery [Figure - 10]. ^[57] Many authors have compared and showed better accuracy of FDG-PET/PET-CT over anatomic imaging modalities for the detection of nodal metastases in the neck. ^[58] FDG PET/CT provides high diagnostic accuracy of 100% compared to 28% alone for CT for residual disease, when performed eight weeks after the conclusion of radiation therapy. ^[59] A positive scan obtained at least six weeks after the end of therapy suggests residual disease, unless there are clinical signs of inflammation/infection to explain the abnormalities on PET. FDG-PET/ PET-CT are also more sensitive and specific in detecting residual and recurrent lymph node metastasis. PET/CT can be used in prognostic stratification and has significant clinical impact on management [Figure - 11]. In a study by Connell CA on 76 patients, the complete metabolic response was predictive of overall survival; it changed radiotherapy planning technique in 29% and altered TNM staging in 34% of the patients. ^[60]

The role of FDG-PET/CT in thyroid cancer should also be stressed. In the evaluation of thyroid incidentalomas, in a large series of patients, it was proven that diffuse thyroid FDG uptake is usually an indicator of chronic thyroiditis. In contrast, focal FDG activity in the thyroid gland has been associated with malignancy. ^[61] FDG-PET/CT may not be a substitute for I-123 or I-131 whole-body scintigraphy in the evaluation of metastatic or recurrent thyroid cancer. However, in patients with increased thyroglobulin levels and negative I-123 or I-131 scan, especially under TSH stimulation, the utility of FDG-PET/CT scan has been confirmed in several studies, and the sensitivity of FDG-PET in detecting metastases in these cases ranges from 71% to 94%. ^{[62],[63],[64]} In patients with medullary thyroid cancer somatostatin receptor scintigraphy may be more sensitive than FDG-PET. However, when fluorine-18 dihydroxyphenylalanine or 8F-DOPA is used, the results are very impressive. ^[65] In this study, it was shown that for lymph node staging the sensitivity was 63% for fluorine-18 dihydroxyphenylalanine PET, 44% for FDG-PET, and 52% for somatostatin receptor scintigraphy. Schwartz et al. demonstrated the excellent role of PET/CT in intensity modulated head and neck radiotherapy, where it can selectively target and intensify the treatment of head and neck cancer while reducing critical normal tissue doses. ^[66]

False Positive: Benign inflammatory/infective diseases show increased lymph node uptake and cause false positive PET/PET-CT results.

False Negative: Head and Neck cancers are usually low-grade tumors and cause false negative results.

Malignant Melanoma

There is no defined role for FDG-PET and PET-CT in the initial diagnosis of melanoma. ^[67] PET is of limited use in patients with early-stage disease without nodal or distant metastases (stage I-II), and sentinel node biopsy is much more sensitive in detecting microscopic lymph node metastases. Recent studies have proved the same with a lower sensitivity as compared to sentinel lymph node biopsy. ^[68] Lymphoscintigraphy and intraoperative mapping with a gamma probe is a better procedure for localizing and dissecting SLN in patients with malignant melanoma. ^[69] However, melanoma metastasizes very widely (to skin, muscle, bone, bowel, myocardium, omentum, leptomeninges, mesentry etc). FDG-PET/CT shows a high tumor-to-background ratio and is therefore useful in this situation as it can highlight metastases at unusual sites that are easily missed with conventional imaging modalities. ^[70] The accuracy of PET in detecting melanoma metastasis ranges from 81-100%. ^[71] FDG-PET/CT is also more accurate than conventional imaging in restaging and follow-up. Iagaru et al. showed that PET/CT has 89% sensitivity and 88% specificity for melanoma lesion detection during restaging, especially in high risk patients. ^[72]

False Negative: PET/PET-CT has limited value for early diagnosis (stage I-II) of the disease. PET is relatively insensitive as compared to SLN biopsy for detection of early nodal disease.

Gastric and Esophageal Cancer

FDG PET/CT is sensitive tool for the staging and restaging of primary gastric and esophageal cancers [Figure - 12]. ^[73] However, the identification of regional nodal metastases has been restricted due to the small volume of disease in some lymph nodes. FDG PET/CT is more specific than CT and endoscopic US for loco-regional lymph node metastasis and response evaluation to neoadjuvant chemotherapy in patients with esophageal carcinoma. ^[74] FDG-PET changed the management in more than 20% of cases. ^[75] Therefore PET is reliable in differentiating resectable and non-resectable disease and avoids many unnecessary surgeries. FDG-PET/CT is more accurate than CT in detection of gastric cancer recurrence after initial surgical resection. Among 23 patients, CT was negative or did not provide definitive information in 11 patients and PET/CT was true positive in all those 11 patients. ^[76]

False Positive: PET/PET-CT has false positive results in patients with inflammatory/infective diseases of esophagus and stomach.

False Negative: PET/PET-CT has limited value for detection of LNs, which are very close to the primary lesion due to a very high uptake in primary and early nodal disease.

Bone Tumors

Diagnostic imaging has played a major role in the evaluation of patients with cancers of bone and soft tissue. MRI is used to define the local extent of osteosarcoma in bone and soft tissue. However, signal abnormalities caused by peritumoral edema can result in an overestimation of tumor extension. FDG-PET and PET-CT may play an important role in determining the metabolic rates of osteosarcoma, guiding biopsy, detecting local recurrence in amputation stumps, evaluating patients with suspected metastatic disease, monitoring response to therapy and assessing for prognosis and differentiating viable sarcoma from post treatment changes. ^[77],[78]

FDG uptake in osteosarcoma has a good correlation with histological grading or tumor aggressiveness. Bastiaannet and coworkers conducted a meta-analysis of 29 clinical studies on the diagnostic value of FDG-PET in the detection, grading, and therapy response of soft tissue and bone sarcomas. ^[79] Eary et al. reported in a meta-analysis of 209 patients that baseline SUV could predict outcome in a better way than conventional grading. ^[80] FDG-PET scan also guides biopsy to the most active tumor metabolic site. Lucas et al. showed that FDG detected more lesions as compared to CT and MRI. ^[81]

In multiple myeloma, bone scan shows marrow involvement indirectly by imaging cortical bone osteoblastic reaction to the marrow tumor while FDG-PET shows marrow involvement directly. Jadvar et al. concluded that FDG-PET could detect early marrow involvement as compared to bone scan and other conventional imaging modalities. PET is also useful in assessing the response to treatment. ^[82]

False Positive: PET/PET-CT has false positive results in patients with acute and chronic osteomyelitis, fractures, trauma, benign bone tumors and bone marrow stimulation.

False Negative: PET/PET-CT has limited value for detection low grade primary bone tumors, lymph nodes which are very close to primary bone tumors due to very high uptake in primary and early nodal disease.

Ovarian Cancer

In two-third of patients, ovarian carcinoma is at an advanced stage at the time of presentation and is one of the deadliest and the most difficult of all gynecologic cancers to control. In patients with ovarian cancer, early lesion localization is difficult with PET alone. However, FDG-PET/CT has high sensitivity and specificity in identifying patients with recurrent tumor. ^[83],[84]

Accurate staging is very important for proper management, especially in patients with raised serum CA-125. FDG-PET/CT has shown high sensitivity and specificity as compared to conventional imaging modalities in detecting lymph node metastases. However, like other imaging modalities, it has a limited role in micro metastases and very small lesions [Figure - 13]. ^[85] Despite this limitation, other studies have suggested that not only the diagnosis of recurrent disease based on PET and PET-CT precedes by the other conventional procedures (median six months) but also that a negative PET scan during the follow-up period after the primary treatment predicts longer relapse free interval than a positive PET scan does. FDG-PET has also been found to be cost-effective in the therapeutic management of patients with ovarian cancer. ^[86]

In one study, diagnostic accuracy of FDG PET/CT was compared with transvaginal ultrasound (TVUS), CECT and histology for ovarian lesion characterization and staging of the disease. PET/CT gave additional value to TVUS for lesion characterization as benign or malignant and PET/CT was superior in staging providing additional lesion sites, compared to CECT. ^[87] There are recent encouraging reports on the utility of combined PET-CT imaging systems for localizing and differentiating pathologic activity from physiologic activity in women with recurrent ovarian carcinoma. ^[88],[89] PET/CT has been evaluated in patients with recurrent ovarian cancer. Bristow et al. evaluated combined PET/CT imaging in 22 patients with epithelial ovarian cancer and rising serum CA-125 levels after primary therapy and negative or equivocal conventional imaging. ^[90] Overall patient-based sensitivity and accuracy of PET/CT in detecting recurrent disease ≥1 cm was 81.8%, with a sensitivity of 83.3% and PPV of 93.8%.

False Positive: PET/PET-CT has false positive results in patients with inflammatory/infective abdominal diseases. Physiological activity in gastrointestinal tract can also cause misinterpretation.

False Negative: PET/PET-CT shows low uptake in mucinous cyst adenocarcinoma. It also has limited value for detection of micrometastases and very small lesions.

Cervical Cancer

Invasive cancer of the cervix is the second most common genital malignancy in women, worldwide. The applications of PET/CT in cervical cancer patients include: assessing metabolic tumor activity and possible endometrial involvement, evaluating pelvic nodal involvement (even in cases with negative CT or MRI studies), detection of distant metastases where it can be used as a first imaging technique, radiation therapy planning of metabolically active lymph nodal lesions, identification of persistent/recurrent disease following neoadjuvant therapy and prognostication in terms of response-survival relationship. ^[91],[92]

Many studies have evaluated the role of FDG-PET in primary staging of cervical cancer and showed a variable sensitivity and specificity. ^[93],[94] A recent meta-analysis by Havrilesky et al. demonstrated a combined pooled sensitivity and specificity of 84% and 95%, respectively, for aortic node metastases, while similar values for pelvic node metastases were 79% and 99%, respectively. ^[95] For recurrent tumor, pooled sensitivity and specificity of 18F-FDG PET were 96% and 81%, respectively. Delayed imaging with FDG-PET can be helpful in extracting more information from FDG-PET. Ma et al. evaluated dual-time point imaging at 40-minute and three-hour intervals. ^[96] The sensitivity, specificity, and accuracy of FDG PET at 40-minute interval were 81.6%, 97.0%, and 91.3%, respectively; and all values increased to 100%, when both the 40-minute and three-hour scans were taken together.

Recent study by Kim et al. compared the value of PET/MRI and PET/CT in detecting lymphonodal recurrence in patients with cervical cancer. PET/MRI detected more additional lesions compared to PET/CT. ^[97] PET/CT also is a good metabolic imaging modality and can prognosticate patients with recurrent cervix cancer [Figure - 14]. Increased uptake (SUV) is directly related to poor prognosis. ^[98] The negative predictive value of PET/CT is very high during restaging of patients especially for para aortic lymph nodal recurrence. ^[99] Sofue et al. evaluated the role of carbon-11 choline PET/CT in the management of uterine carcinoma in 22 patients, of which five patients were also available for treatment response assessment. They found that carbon-11 choline PET/CT was good for tumor, nodal and metastatic saging, as well as SUV reduction was remarkable in five patients after receiving treatment. ^[100]

FDG-PET has been evaluated for treatment planning in cervical cancer patients. Grigsby et al. evaluated patients with cervical cancer and negative lymph nodes diagnosed by FDG-PET. ^[101] Sixty-five patients were studied in two groups, one that was treated with irradiation (RT) and concurrent chemotherapy and second with RT alone. The five-year overall survival estimate was 81% with RT and concurrent chemotherapy and 85% with RT alone. Intensity-modulated radiotherapy (IMRT), guided by PET/CT has been evaluated. Esthappan et al. studied PET/CT guided IMRT for para-aortic lymph nodes in patients with cervical cancer para-aortic metastasis. ^[102]

False Positive: PET/PET-CT has false positive results in patients with infected fibroid, cervicitis and other inflammatory/infective pathologies. Increased FDG uptake is also noted during menstrual cycle.

False Negative: PET/PET-CT has limited value in detection of primary cervical cancer in early stages and disease activity in pelvic LNs.

Pancreatic Cancer

FDG-PET/CT has been extensively evaluated for pancreatic cancer in initial staging and restaging as well as primary pancreatic mass diagnosis. ^{[103],[104],[105]} FDG-PET/CT in pancreatic cancer is mainly indicated for staging by detecting CT-occult metastases, detecting recurrence, and monitoring therapy and for the diagnosis in patients with suspected pancreatic cancer in equivocal CT or non-diagnostic FNAs. ^[103] An important aspect in pancreatic imaging is differentiation of pancreatic cancer and benign lesions especially in patients of chronic pancreatitis. Nitzsche et al. evaluated non-invasive differentiation between pancreatic cancer and chronic pancreatitis using FDG-PET. ^[106] They found that dynamic FDG PET study, including kinetic analysis, yields more accurate results than semi quantitative analysis of pancreatic lesions. Sperti et al. studied the role of FDG-PET in differentiating malignant from benign cystic lesions. ^[107] In detecting malignancy in cystic lesions, the accuracy of FDG-PET was 94% and was clearly superior to conventional CT (accuracy 80%). In the present scenario, FDG-PET is considered as a complementary study in pancreatic cancer, especially when CT is non-diagnostic.

FDG-PET/CT may reveal unsuspected metastases to the liver, bones and lungs, thereby changing the management protocol. FDG-PET/CT has been shown to be an effective imaging modality in detecting occult distant metastasis in patients with pancreatic cancer and thus changing patient management. ^[108] In a recent study by Farm JM, PET/CT had sensitivity of 87% for metastatic lesion detection and changed management in 11% of the patients by detecting occult lesions not detected by CT alone. ^[103] In a study by Tang et al, FDG PET/CT and endoscopic ultrasound was compared for the diagnosis of primary pancreatic carcinoma. FDG PET/CT was more sensitive and endoscopic ultrasound was more specific for the primary diagnosis of pancreatic cancer. ^[105] One pilot study compared the value of FLT PET/CT and FDG PET/CT in primary pancreatic cancer diagnosis in five patients. FLT PET/CT showed localized in only two of five patients with low SUV and FDG was positive in all patients with high SUV. ^[109] FDG-PET shows markedly reduced uptake early after the treatment, when there was no definite change in tumor size on CT. ^[110]

False Positive: PET/PET-CT has false positive results in patients with acute and chronic pancreatitis and pancreatic cyst.

False Negative: False-negative findings are note in patients with insulin-dependent diabetes, mucinous adenocarcinoma, neuroendocrine tumors of pancreas.

Hepatocellular Carcinoma

The role of FDG-PET/CT is limited in hepatocellular carcinoma (HCC). It is mainly indicated in patients with moderately or poorly differentiated HCC, tumors> 5 cm, or with markedly elevated AFP levels. ^[111],[112] Owing to the variable activity of the enzyme glucose-6-phosphatase in the hepatocytes in patients with HCC, there is a varying degree of accumulation of FDG. Consequently, FDG-PET imaging can have three different patterns, namely higher uptake, equivocal uptake and lower uptake, compared to normal liver background [Figure - 15]. Khan et al. demonstrated lower sensitivity of FDG-PET in the diagnosis of HCC than CT. ^[113] They also found that well differentiated and low-grade liver tumors had lower FDG uptake. Most recurrences in HCC are intrahepatic. However, 30% of the recurrences are extra hepatic. The role of resection in intrahepatic recurrences is widely accepted. The role of resection in extra hepatic HCC recurrence and metastasis is not well established. FDG PET/CT appears to be useful in detecting distant metastasis as well as portal vein invasion and thus has impact on management. ^[114] The FDG uptake in HCC has been correlated well with prognosis. Higher SUVs are associated with poor prognosis.

Recently, C11-Acetate has been studied as a radiotracer for PET imaging in patients with HCC. ^[115],[116] Park et al. found that C11-acetate successfully detected well-differentiated HCC, while the poorly differentiated HCCs were efficiently detected by F18-FDG. Patients who were positive on FDG PET/CT had overall lower survival rate compared to 11C-acetate. 11C-Acetate and FDG PET/CT were complementary in primary disease detection, however no significant change seen in extra hepatic metastatic lesion detection. ^[116] 11C-acetate had a sensitivity of 87.3% for detection of HCC in patients with localized disease and ≤3 lesions, which was clearly superior to FDG-PET (sensitivity 47.3%) in the same group of patients. In patients with diffuse or multifocal diseases, the two imaging modalities were complementary to each other in majority of the cases.

False Positive: Liver abscess and inflammatory/infective liver diseases leads to false positive results.

False Negative: PET/PET-CT shows variable FDG uptake due to glucose-6-phosphatase enzyme in the hepatocytes in liver diseases and tumor grading.

Gastrointestinal Stromal Tumors

Gastrointestinal Stromal Tumors (GISTs) are a subset of mesenchymal tumors of the gastrointestinal tract, occurring in the stomach in 70% of cases. CT scanning is the imaging modality of choice in GISTs, which can locate a mass lesion, contiguous organ invasion and distant metastases. FDG-PET/CT in GISTs is being used widely since the introduction of imatinib mesylate. As FDG-PET is a functional imaging study, it may be expected to be useful in rapid evaluation of response to imatinib. It may show significant drop in FDG uptake early after imatinib therapy, while on conventional anatomical imaging, tumor size may remain constant for an indefinite period of time. FDG-PET/CT improves staging, accurately separates responders from non-responders in an early stage, and is helpful during follow-up. Several studies have shown superiority of FDG-PET over conventional imaging modalities in determining response to therapy in patients with GISTs. ^[117],[118] Kamiyama et al. evaluated the role of FDG-PET in predicting the malignant potential of gastric stromal tumors before surgery. ^[119] They found a significant correlation between FDG uptake and the mitotic index, indicating the value of FDG-PET in predicting malignant potential in these patients.

False Positive: PET/PET-CT has false positive results in patients with inflammatory/infective abdominal diseases. Physiological activity in gastrointestinal tract can also cause misinterpretation.

Prostate Cancer

The most effective screening tools for prostate cancer are digital rectal examination (DRE) and serum prostate specific antigen (PSA) monitoring. The role of FDG-PET in prostate cancer localized within the gland is limited owing to low metabolic behavior shown by this tumor and urinary excretion of FDG. ^[120] It is also not very useful in differentiating hypertrophy from cancer, a major obstacle in the diagnosis of prostate cancer. ^[120],[121] Oyama et al. found FDG-PET to be an insensitive method to detect prostate cancer. ^[122] However, FDG uptake correlates well with PSA levels as a measure of tumor size, advanced tumor or PSA relapse. ^[121] 11C-choline PET/CT has variable results for recurrent or residual disease localization. Reske et al. did 11C-choline PET/CT on 49 patients with biochemical evidence of recurrence and found 71% sensitive for local recurrence and all patients showed biochemical response following local treatment. ^[123]

In detecting soft-tissue metastasis to pelvic lymph nodes, FDG-PET has a limited role, owing to urinary excretion of FDG through kidneys and low glucose metabolism by tumor cells. ^[124] Shreve et al. compared FDG-PET imaging with CT scan and bone scintigraphy. ^[124] They found that pelvic lymph node detection was severely limited by bladder activity and streak artifacts. In osseous metastasis too, the use of FDG-PET is limited. However, PET-CT is very useful and can demonstrate sclerotic bone metastases [Figure - 16]. A recent study by Garcia compares 11C-choline and FDG PET/CT in 38 surgically operated patients; 11C-choline appeared to be significantly more sensitive than FDG imaging in detecting recurrence at prostate bed, pelvic lymph nodes as well as for distant metastases. Sensitivity of 11C-choline was progressively increased with the increase in the PSA levels. ^[125] However, FDG-PET can be useful when conventional imaging methods like bone scanning, show equivocal or negative results, especially in progressively metastatic tumors. We feel that bone scan and PET are complimentary modalities for the detection of bone metastases in these patients.

Bladder Tumors

The role of FDG-PET/CT in bladder cancer is evolving and very limited work has been done in the recent past. Urinary excretion of FDG and streak artifacts from excreted tracer in the bladder has contributed to the limited value of FDG-PET in bladder cancer for the primary tumor localization. ^[121] However, it can be useful if special views are obtained. We have introduced special technique for such patients [Figure - 17]. In a recent prospective study, Kibel et al. did FDG PET/CT in 43 patients for initial staging before cystectomy and all had negative CT and bone scintigraphy. FDG-PET/CT demonstrated a positive predictive value of 78%, a negative predictive value of 91%, sensitivity of 70%, and specificity of 94%. Recurrence-free survival, disease-free survival and overall survival were all significantly poorer in the patients with positive FDG-PET/CT than in those with negative FDG-PET/CT. ^[126] De Jong et al. have tried a new radiotracer 11C-choline with PET, in patients with bladder cancer. ^[127] They found avid uptake of choline in bladder cancer with virtual absence of urinary radioactivity, while there was no uptake in pre-malignant lesions or small non-invasive tumors.

Renal Cancer

As the excretory route of FDG is mainly renal, the role of FDG-PET is chiefly in metastatic renal cancer to evaluate the other sites of disease. Studies have shown wide variability in characterization and staging of renal cell carcinoma, with sensitivities ranging from 40% to 100%. ^[128] Diuresis has been suggested to increase the contrast between the tumor and background renal tissue. ^[129] However, no significant correlation was found between diuretic use and improvement of the FDG-PET sensitivity. Kang et al. evaluated 66 patients with renal cancer and found that PET detected primary renal tumors with a sensitivity of 60% and specificity of 100%. ^[130] In a recent work, Kumar et al. studied the role of FDG-PET in solid renal masses. ^[131] In this study, FDG-PET accurately detected 85% (23 of 27) of malignant renal lesions. Studies have shown a complimentary role of FDG-PET to the conventional imaging methods, in detecting distant metastasis [Figure - 18]. PET/CT has promising results for assessment of sumitinib treatment response in patients with metastatic renal cell carcinoma. In one study by Vercellino et al. PET/CT was used to assess the metabolic response of sunitinib an antiangiogenic agent in patients with metastatic renal cell carcinoma. ^[132]

False Positive: PET/PET-CT has false positive results in patients with infective/inflammatory diseases.

False Negative: PET/PET-CT has limited value in detection of primary prostatic and renal malignancies in early stages and disease activity in pelvic LNs, due physiological excretion of FDG through kidneys in to urinary bladder.

Testicular Cancer

Among urological tumors, FDG-PET is most useful in testicular cancers, especially in defining recurrent and residual masses and in patients with raised markers. Many authors have evaluated the role of FDG-PET for initial staging and produced variable results. ^{[133],[134],[135],[136]} Tsatalpas et al. compare PET and CT in 32 patients with testicular cancer. ^[134] Though not statistically significant, FDG-PET was found superior to CT scan in detecting metastatic infradiaphragmatic and supradiaphragmatic lesions. In a recent study, Lassen et al. studied the role of FDG-PET in Stage I non-seminomatous germ cell tumors, with normal findings on conventional imaging. ^[136] FDG-PET was superior to conventional imaging modalities, with sensitivity, specificity, accuracy, NPV and PPV of 70%, 100%, 93%, 92% and 100% respectively. FDG-PET has been evaluated for its role in testicular tumor recurrence or relapse. ^[137] De Santis et al. evaluated residual testicular tumor with FDG-PET. ^[138] They found that all residual lesions more than 3 cm and 96% of lesions less than or equal to 3 cm were correctly predicted by FDG PET. In their recent work, Becherer et al. find that in post-chemotherapy residual seminomas the specificity of PET was significantly higher than that of CT when using a ≥ 3 cm cutoff [Figure - 19]. ^[139] Therefore, FDG-PET may contribute to the management plan of residual seminoma lesions, as it can avoid unnecessary additional treatment, especially when tumor size is ≥ 3 cm.

Neuroendocrine Tumors

Functional imaging has a great role in neuroendocrine tumors as it targets the molecular characteristics of endocrine tumors. The role of PET in neuroendocrine tumors is continuously and rapidly increasing as a complementary and valuable diagnostic tool, particularly when other imaging modalities have failed. ^[140] However, as opposed to other malignancies where FDG is the most commonly used positron-emitting radiotracer for PET imaging, in NET, other positron-emitting radionuclides, are more successfully employed. These include 11C-Hydroxyephedrine, 11C-Epinephrine, 11C-5-hydroxytryptophan, 18F-DOPA, 68 gallium-DOTA TOC and DOTA NOC. ^[141]

Pheochromocytomas and Paragangliomas

FDG-PET has been used in phaeochromocytoma as an adjunct to other imaging modalities. FDG-PET helps in localizing majority of the pheochromocytomas as most of these tumors accumulate FDG. However, FDG-PET has been described to have lower sensitivity and also lower specificity due to accumulation of glucose by a variety of other neoplastic and non-neoplastic processes. ^[141] Studies have found 18F-DOPA whole-body PET to be highly sensitive and specific for detection of pheochromocytomas and paragangliomas and monitoring the response to therapy; ^[142],[143] 18F-DOPA-PET also helps in detecting metastasis from malignant pheochromocytomas, especially when used after negative MIBG study. ^[144],[145] Trampal et al. studied the role of 11C-hydroxyephedrine-PET in pheochromocytomas and found it to be highly sensitive and specific. ^[146] We have performed 68 Gallium68- DOTA TOC and DOTA NOC PET-CT in these patients and found encouraging results [Figure - 20]. We feel that PET, MIBG and Somatostatin receptor scintigraphy have a complimentary role in the management of these tumors.

Carcinoid Tumors

Carcinoid tumors are difficult to diagnose in earlier stages because of their small size and low proliferation rate. CT is mainly used for characterizing and staging of the tumor. Somatostatin receptor scintigraphy (SRS) is the functional imaging study used for detection and staging of carcinoid tumors. Unfortunately, the role of FDG-PET is limited in carcinoid tumors due to their low proliferative activity and high differentiation rate. ^[147] Therefore, other PET radiotracers like F18-DOPA and C11-labeled 5-HTP have been studied, which are specifically directed towards the carcinoid tumors. ^[141] Hoegerle et al. studied the role of F18-DOPA in gastrointestinal carcinoid tumors in a series of 17 patients. They found PET to be a promising procedure and a useful supplement to morphologic methods in diagnostic imaging of gastrointestinal carcinoid tumors. ^[148] Various studies have shown promising results of 68 gallium-DOTA TOC and DOTA NOC in bronchial and gastrointestinal carcinoids. ^[149],[150] We feel that PET, MIBG and Somatostatin receptor scintigraphy have a complimentary role in the management of these tumors.

Adrenocortical Tumors

Tumors of the adrenal cortex may present with Cushing′s syndrome, feminization, virilization, hyperaldosteronism (hypertension), hypoglycemia, mixed hormone excess syndrome or sometimes, with no recognizable features. The diagnosis depends upon the level of hormonal metabolites in blood/urine and localization of adrenal mass on CT/MRI. Functional studies, e.g. adrenocortical scintigraphy, mostly use radiopharmaceuticals, which are analogs of cholesterol, thereby, acting as a substrate for adrenal steroid hormone synthesis. FDG-PET is a useful functional imaging modality for detection of primary adrenocortical cancer and metastatic lesions. ^[151],[152] FDG-PET has been shown to have excellent diagnostic performance (sensitivity 93% and specificity 90%) in differentiating adrenal lesions detected on CT or MRI in patients with known malignancies. ^[151] FDG PET has the additional advantage of evaluating primary lesions as well as metastases. ^{[153],[154],[155]} Recently, C11-Etomidate and C11-metomidate have been used effectively as tracers in PET imaging to distinguish adrenocortical tumor from metastatic cancer based on targeting of specific enzyme (11ί-hydroxylase) involved in cortisol and aldosterone synthesis. ^[156],[157] However, this does not allow differentiation of benign from malignant adrenocortical lesions.

Brain Tumors

The role of FDG-PET in brain tumors is chiefly in gliomas, the most frequently occurring primary brain tumors. FDG-PET is basically a measure of glucose uptake and mainly utilized for grading tumors, distinguishing tumor from necrosis, or other post-radiation effects. ^[158] Increased FDG uptake has been correlated with tumor grade, tumor cell density, biological aggressiveness, and survival of patients in primary as well as recurrent gliomas. ^[159],[160] However, studies have demonstrated diagnostic limitations of FDG PET for imaging brain tumors, mainly due to difficulty in characterizing tumors in the brain, owing to high glucose uptake of normal brain tissue. Spence et al. evaluated whether distinction between tumor and normal gray matter is improved by delayed imaging and found that tumor enhancement was greater than enhancement of surrounding brain regions at later imaging times. ^[160]

New radiotracers like C11-methionine (C11-MET), C11-tyrosine, F18-fluoro-tyrosine, F18-fluoroethyl-tyrosine (F18-FET), 8-cyclopentyl-3-(3-18F-fluoropropyl)-1-propylxanthine (F18-CPFPX) and F18-fluoro-thymidine (F18-FLT) have been studied for PET imaging in brain tumors. ^{[158],[159],[160]} These new agents are different from the traditional FDG in that the normal brain uptake of these compounds is lower than that of the FDG. MET-PET was particularly useful for low-grade gliomas. Dysembryoplastic neuroepithelial tumors mainly associated with longstanding epilepsy, show normal MET-PET uptake in majority of the cases, while other tumors like gliomas or gangliogliomas show moderate or high MET uptake. ^[161]

Other newer radiotracers have also been used to characterize primary brain tumors and have a promising role in the future. 18F-FLT-PET and F18-CPFPX-PET have been specifically used to image cellular proliferation in brain tumors. ^[162] F18-FET-PET has been evaluated in characterizing brain tumors. ^[162],[163] Pauleit et al. demonstrated that sensitivity and specificity of MRI changed from 96% and 53%, respectively to 93% and 94%, respectively, when combined with FET-PET. ^[164]

False Positive: PET/PET-CT has false positive results in patients with infective/inflammatory brain diseases.

False Negative: PET/PET-CT has limited value in detection of low and moderate grade primary brain tumors due physiological FDG uptake in brain.

References

Copyright 2010 - Indian Journal of Cancer

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